Cell migration is an essential process involved in important physiological processes such as embryogenesis1, angiogenesis2, wound healing3 and the immune response4. Unfortunately, cell migration is also involved in many pathologies, including cancer metastasis5 and inflammation6. In each of these physiological and pathological processes, the basic process of cell migration, i.e. translocation along or through a tissue substrate, is the same.
Cells migrate in different modes depending on the type and function of the cells. Leukocytes, for example, migrate the majority of their life span as single cells within virtually any tissue in the body.4 Many other cell types only move at specific situations to place, shape or repair tissue. Most of these cells move in groups that are loosely or closely associated. This type of migration is called collective cell migration.
In this article, different modes of both single cell migration and collective cell migration are discussed.
General migration process
The basic process of cell migration all starts with cells having a directional polarity, with a leading edge and a trailing end. Subsequently, actomyosin mediated protrusions form at the leading edge followed by attachment of the protrusions to the substrate by the formation of integrin-based focal adhesions7–9. Actomyosin contraction leads to tension along the length axis of the cells, which in turn causes translocation of the cell body forward and retraction of the trailing end7–9. This basic process is relevant in most cell types and types of cell migration. However, each cell and migration type has its own specific variant (even depending on the cell environment), which can differ in terms of cell morphology, migration speed, cell-cell interactions and dynamics7,9.
Roughly speaking, cell migration can be categorized into single cell migration and collective cell migration. Which each consist of several different types of migration (Fig. 1). Next to migration, cells can also display invasion. The difference between the two being that the surrounding environment is restructured by the cells in case of invasion. In the next paragraphs, single cell migration, collective cell migration and cell invasion are discussed in more detail.
Single cell migration
Single cell migration can roughly be divided into amoeboid and mesenchymal migration (Fig. 1). The first form of ameboid migration is called blebby amoeboid migration and is characterized by movement of rounded or ellipsoid cells without mature focal adhesions and filopodia.7,10 These blebby cells do not migrate by adhering or pulling on the substrate but rather use propulsive, pushing blebs.11 This type of migration is used by e.g. leukocytes migrating through ECM.4
Pseudopodal ameboid migration is the second form of ameboid migration and is defined by displacement of more elongated cells having weak cell-substrate interactions and actin-rich filopodia at their leading edge.10,12 Neutrophils and dendritic cells, for example, display this type of migration13.
Elongated, spindle-like, cells with strong focal adhesions and high cytoskeletal (actomyosin) contractility move using mesenchymal migration12,14. This type of migration mostly resembles the general type of migration described in section 2.1. and is seen in cells such as fibroblasts15 and sarcoma cells16.
Figure 1. Overview of different modes of cell migration. These modes are named based on the cell morphology during migration. Orange cells represent different modes of single cell migration, purple cells represent different modes of collective migration. Cell-cell contacts are displayed in pink.
For researchers interested in creating time-lapse videos from within cell culture incubators or hypoxia chambers, we recommend the CytoSMART Lux2 Duo Kit.
Collective cell migration
Collective cell migration is characterized by the coordinated migration of a group of cells in which cells are influenced by interactions with each other. The exact definition of collective cell migration is still open for debate. Some argue that stable cell-cell junctions are required for collective cell migration17,18. Others suggest that migration can be considered collective when cells moving as a group affect each other’s movement by e.g. forming transient cell-cell contacts or secreting soluble factors 9,19. Here, we comply with the latter definition and consider migration to be collective when some form of cell-cell interaction is displayed in a migrating group of cells. In that case, when looking at the extreme ends of the spectrum, collective cell migration can be split into collective migration of epithelial cells and of mesenchymal cells (Fig. 1).19 However, any intermediate between epithelial and mesenchymal collective cell migration can take place depending on cell type and state (e.g. level of Epithelial to Mesenchymal Transition (EMT)20).
Epithelial cells form cell-cell adhesions (adherens junctions, desmosomes, tight junctions and gap junctions) in order to fulfill their barrier function.21 During collective migration, epithelial cells maintain stable cell-cell adhesions, thus still fulfilling their barrier function.19,22,23 Epithelial cells can undergo collective migration in several manners. Examples of collective epithelial cell migration are the formation of sprouts or branches as seen in neo-angiogenesis of blood vessels24 and branching morphogenesis of mammary glands25. Epithelial cells can also migrate as separate groups of cells like the border cells in Drosophila egg chambers26 or invasive groups of detached cancer cells27. Another form of epithelial cell migration is the migration of strands stretching out of a tissue such as those observed in invasive carcinomas28. However, the most studied form of epithelial collective migration is that of sheet migration where cells migrate as a 2D interconnected sheet. Sheet migration is seen during wound healing, both in skin22 and in other epithelial tissues such as the intestine29 and cornea30. The common denominator between all these types of collective migration is that they rely on mechanical coupling of the cells via stable cell-cell adhesions.19,22,23 These adhesions ensure coordinated cytoskeletal activity of all cells within the collective. In this manner, the group of cells can obtain a polarity and thus directionality at the collective level, similar to the polarity needed for migration at the single cell level.
In contrast to the tightly connected epithelial cells, mesenchymal cells only form transient connections with each other. When two polarized mesenchymal cells collide, they form (N-cadherin based) cell-cell adhesions. This triggers the retraction of the cell protrusions (lamellipodia and/or filopodia), causing a loss in polarity. This subsequently halts the migration and the cells quickly repolarize in the opposite direction. The repolarization causes the cells to move away from each other. This process is called contact-inhibition of locomotion (CIL) and can occur between cells of the same type (homotypic CIL) or between two different cell types (heterotypic CIL)31,32. Recent studies have shown that loss of heterotypic CIL is involved in cancer metastasis and invasion.33–35 Next to CIL, cells actively attract each other by secreting attractants (co-attraction).19 In the case of neural crest cells, for example, C3a is secreted, which is a well-known attractant in the immune system.36 Since each cell in the group produces the same attractant, the attractant concentration is high in regions with a high cell density. When a cell moves away from the group due to CIL, it can migrate back to the collective by following the local gradient of chemo-attractant (e.g. C3a gradient)19. It is assumed that this continues cycle of repulsion and attraction via respectively CIL and co-attraction maintains the collective migration of mesenchymal cells. Collective mesenchymal migration has mainly been studied in neural crest cells36–38, but recent studies show that this type of migration is also involved in many other processes such as cancer metastasis33,39 and the migration of the mesoderm during development40.
More in depth information about collective migration of epithelial and mesenchymal cells (including CIL) can be found in excellent reviews by Friedl and Gilmour18, Friedl and Mayor23, Rorth9, Roycroft and Mayor31, Scarpa and Mayor1, Stramer and Mayor32 and Theveneau and Mayor19.
For researchers interested in creating whole-well time lapse videos, we recommend the CytoSMART Omni. This automated live-cell imaging system operates from within cell culture incubators and can be used for hours, days or weeks at a time.
Migration versus invasion
Next to migrating inside the body, cells can also invade their surrounding environment. In biology, the terms migration and invasion are often used as interchangeable phrases. While the mechanisms are closely related, cell migration is defined as the directed translocation of cells on a 2D substrate or through a 3D matrix. Cell invasion, on the other hand is defined as cell movement through a 3D matrix, which is accompanied by restructuring the 3D environment.5,8 The process of cell invasion encompasses cell adherence to extracellular matrix (ECM) and subsequent remodeling of the ECM by means of degradation of existing ECM components and deposition of new ECM components before being able to migrate through the ECM.5,8 Thus the term invasion describes a specific mode of 3D migration including ECM degradation whereas migration is used to describe non-destructive movement in both 2D and 3D environments.
Dr. Inge Thijssen-van Loosdregt
(1) Scarpa, E.; Mayor, R. Collective Cell Migration in Development. J. Cell Biol. 2016, 212 (2), 143–155. https://doi.org/10.1083/jcb.201508047.
(2) Lamalice, L.; Le Boeuf, F.; Huot, J. Endothelial Cell Migration During Angiogenesis. Circulation Research 2007, 100 (6), 782–794. https://doi.org/10.1161/01.RES.0000259593.07661.1e.
(3) Qing, C. The Molecular Biology in Wound Healing & Non-Healing Wound. Chinese Journal of Traumatology 2017, 20 (4), 189–193. https://doi.org/10.1016/j.cjtee.2017.06.001.
(4) Friedl, P.; Weigelin, B. Interstitial Leukocyte Migration and Immune Function. Nat Immunol 2008, 9 (9), 960–969. https://doi.org/10.1038/ni.f.212.
(5) van Roosmalen, W.; Le Dévédec, S. E.; Golani, O.; Smid, M.; Pulyakhina, I.; Timmermans, A. M.; Look, M. P.; Zi, D.; Pont, C.; de Graauw, M.; Naffar-Abu-Amara, S.; Kirsanova, C.; Rustici, G.; Hoen, P. A. C. ‘t; Martens, J. W. M.; Foekens, J. A.; Geiger, B.; van de Water, B. Tumor Cell Migration Screen Identifies SRPK1 as Breast Cancer Metastasis Determinant. J. Clin. Invest. 2015, 125 (4), 1648–1664. https://doi.org/10.1172/JCI74440.
(6) Luster, A. D.; Alon, R.; von Andrian, U. H. Immune Cell Migration in Inflammation: Present and Future Therapeutic Targets. Nat Immunol 2005, 6 (12), 1182–1190. https://doi.org/10.1038/ni1275.
(7) Friedl, P.; Wolf, K. Tumour-Cell Invasion and Migration: Diversity and Escape Mechanisms. Nat Rev Cancer 2003, 3 (5), 362–374. https://doi.org/10.1038/nrc1075.
(8) Ilina, O.; Friedl, P. Mechanisms of Collective Cell Migration at a Glance. Journal of Cell Science 2009, 122 (18), 3203–3208. https://doi.org/10.1242/jcs.036525.
(9) Rørth, P. Collective Cell Migration. Annu. Rev. Cell Dev. Biol. 2009, 25 (1), 407–429. https://doi.org/10.1146/annurev.cellbio.042308.113231.
(10) Lämmermann, T.; Sixt, M. Mechanical Modes of ‘Amoeboid’ Cell Migration. Current Opinion in Cell Biology 2009, 21 (5), 636–644. https://doi.org/10.1016/j.ceb.2009.05.003.
(11) Fackler, O. T.; Grosse, R. Cell Motility through Plasma Membrane Blebbing. Journal of Cell Biology 2008, 181 (6), 879–884. https://doi.org/10.1083/jcb.200802081.
(12) Friedl, P.; Wolf, K. Plasticity of Cell Migration: A Multiscale Tuning Model. J Cell Biol 2010, 188 (1), 11–19. https://doi.org/10.1083/jcb.200909003.
(13) Renkawitz, J.; Kopf, A.; Stopp, J.; de Vries, I.; Driscoll, M. K.; Merrin, J.; Hauschild, R.; Welf, E. S.; Danuser, G.; Fiolka, R.; Sixt, M. Nuclear Positioning Facilitates Amoeboid Migration along the Path of Least Resistance. Nature 2019, 568 (7753), 546–550. https://doi.org/10.1038/s41586-019-1087-5.
(14) Ridley, A. J. Cell Migration: Integrating Signals from Front to Back. Science 2003, 302 (5651), 1704–1709. https://doi.org/10.1126/science.1092053.
(15) Acharya, P. S.; Majumdar, S.; Jacob, M.; Hayden, J.; Mrass, P.; Weninger, W.; Assoian, R. K.; Pure, E. Fibroblast Migration Is Mediated by CD44-Dependent TGF Activation. Journal of Cell Science 2008, 121 (9), 1393–1402. https://doi.org/10.1242/jcs.021683.
(16) Shor, A. C.; Keschman, E. A.; Lee, F. Y.; Muro-Cacho, C.; Letson, G. D.; Trent, J. C.; Pledger, W. J.; Jove, R. Dasatinib Inhibits Migration and Invasion in Diverse Human Sarcoma Cell Lines and Induces Apoptosis in Bone Sarcoma Cells Dependent on Src Kinase for Survival. Cancer Research 2007, 67 (6), 2800–2808. https://doi.org/10.1158/0008-5472.CAN-06-3469.
(17) Kramer, N.; Walzl, A.; Unger, C.; Rosner, M.; Krupitza, G.; Hengstschläger, M.; Dolznig, H. In Vitro Cell Migration and Invasion Assays. Mutation Research/Reviews in Mutation Research 2013, 752 (1), 10–24. https://doi.org/10.1016/j.mrrev.2012.08.001.
(18) Friedl, P.; Gilmour, D. Collective Cell Migration in Morphogenesis, Regeneration and Cancer. Nat Rev Mol Cell Biol 2009, 10 (7), 445–457. https://doi.org/10.1038/nrm2720.
(19) Theveneau, E.; Mayor, R. Collective Cell Migration of Epithelial and Mesenchymal Cells. Cell. Mol. Life Sci. 2013, 70 (19), 3481–3492. https://doi.org/10.1007/s00018-012-1251-7.
(20) Campbell, K.; Casanova, J. A Common Framework for EMT and Collective Cell Migration. Development 2016, 143 (23), 4291–4300. https://doi.org/10.1242/dev.139071.
(21) Edelblum, K. L.; Turner, J. R. Epithelial Cells. In Mucosal Immunology; Elsevier, 2015; pp 187–210. https://doi.org/10.1016/B978-0-12-415847-4.00012-4.
(22) Das, T.; Safferling, K.; Rausch, S.; Grabe, N.; Boehm, H.; Spatz, J. P. A Molecular Mechanotransduction Pathway Regulates Collective Migration of Epithelial Cells. Nat Cell Biol 2015, 17 (3), 276–287. https://doi.org/10.1038/ncb3115.
(23) Friedl, P.; Mayor, R. Tuning Collective Cell Migration by Cell–Cell Junction Regulation. Cold Spring Harb Perspect Biol 2017, 9 (4), a029199. https://doi.org/10.1101/cshperspect.a029199.
(24) Hamm, M. J.; Kirchmaier, B. C.; Herzog, W. Sema3d Controls Collective Endothelial Cell Migration by Distinct Mechanisms via Nrp1 and PlxnD1. Journal of Cell Biology 2016, 215 (3), 415–430. https://doi.org/10.1083/jcb.201603100.
(25) Ewald, A. J.; Brenot, A.; Duong, M.; Chan, B. S.; Werb, Z. Collective Epithelial Migration and Cell Rearrangements Drive Mammary Branching Morphogenesis. Developmental Cell 2008, 14 (4), 570–581. https://doi.org/10.1016/j.devcel.2008.03.003.
(26) Lin, T.-H.; Yeh, T.-H.; Wang, T.-W.; Yu, J.-Y. The Hippo Pathway Controls Border Cell Migration Through Distinct Mechanisms in Outer Border Cells and Polar Cells of the Drosophila Ovary. Genetics 2014, 198 (3), 1087–1099. https://doi.org/10.1534/genetics.114.167346.
(27) Cheung, K. J.; Padmanaban, V.; Silvestri, V.; Schipper, K.; Cohen, J. D.; Fairchild, A. N.; Gorin, M. A.; Verdone, J. E.; Pienta, K. J.; Bader, J. S.; Ewald, A. J. Polyclonal Breast Cancer Metastases Arise from Collective Dissemination of Keratin 14-Expressing Tumor Cell Clusters. Proc Natl Acad Sci USA 2016, 113 (7), E854–E863. https://doi.org/10.1073/pnas.1508541113.
(28) Haeger, A.; Alexander, S.; Vullings, M.; Kaiser, F. M. P.; Veelken, C.; Flucke, U.; Koehl, G. E.; Hirschberg, M.; Flentje, M.; Hoffman, R. M.; Geissler, E. K.; Kissler, S.; Friedl, P. Collective Cancer Invasion Forms an Integrin-Dependent Radioresistant Niche. Journal of Experimental Medicine 2020, 217 (1), e20181184. https://doi.org/10.1084/jem.20181184.
(29) Sturm, A.; Sudermann, T.; Schulte, K.; Goebell, H.; Dignass, A. U. Modulation of Intestinal Epithelial Wound Healing in Vitro and in Vivo by Lysophosphatidic Acid. Gastroenterology 1999, 117 (2), 368–377. https://doi.org/10.1053/gast.1999.0029900368.
(30) de Medeiros, F. W.; Wilson, S. E. Wound Healing after Laser in Situ Keratomileusis and Photorefractive Keratectomy. In Ocular Disease; Elsevier, 2010; pp 16–21. https://doi.org/10.1016/B978-0-7020-2983-7.00003-6.
(31) Roycroft, A.; Mayor, R. Molecular Basis of Contact Inhibition of Locomotion. Cell. Mol. Life Sci. 2016, 73 (6), 1119–1130. https://doi.org/10.1007/s00018-015-2090-0.
(32) Stramer, B.; Mayor, R. Mechanisms and in Vivo Functions of Contact Inhibition of Locomotion. Nat Rev Mol Cell Biol 2017, 18 (1), 43–55. https://doi.org/10.1038/nrm.2016.118.
(33) Tanaka, M.; Kuriyama, S.; Aiba, N. Nm23-H1 Regulates Contact Inhibition of Locomotion, Which Is Affected by Ephrin-B1. Journal of Cell Science 2012, 125 (18), 4343–4353. https://doi.org/10.1242/jcs.104083.
(34) Batson, J.; Astin, J. W.; Nobes, C. D. Regulation of Contact Inhibition of Locomotion by Eph-Ephrin Signalling: REGULATION OF CONTACT INHIBITION OF LOCOMOTION BY EPH-EPHRIN SIGNALLING. Journal of Microscopy 2013, 251 (3), 232–241. https://doi.org/10.1111/jmi.12024.
(35) Lin, B.; Yin, T.; Wu, Y. I.; Inoue, T.; Levchenko, A. Interplay between Chemotaxis and Contact Inhibition of Locomotion Determines Exploratory Cell Migration. Nat Commun 2015, 6 (1), 6619. https://doi.org/10.1038/ncomms7619.
(36) Carmona-Fontaine, C.; Theveneau, E.; Tzekou, A.; Tada, M.; Woods, M.; Page, K. M.; Parsons, M.; Lambris, J. D.; Mayor, R. Complement Fragment C3a Controls Mutual Cell Attraction during Collective Cell Migration. Developmental Cell 2011, 21 (6), 1026–1037. https://doi.org/10.1016/j.devcel.2011.10.012.
(37) Theveneau, E.; Mayor, R. Can Mesenchymal Cells Undergo Collective Cell Migration? The Case of the Neural Crest: The Case of the Neural Crest. Cell Adhesion & Migration 2011, 5 (6), 490–498. https://doi.org/10.4161/cam.5.6.18623.
(38) Szabó, A.; Mayor, R. Cell Traction in Collective Cell Migration and Morphogenesis: The Chase and Run Mechanism. Cell Adhesion & Migration 2015, 9 (5), 380–383. https://doi.org/10.1080/19336918.2015.1019997.
(39) te Boekhorst, V.; Friedl, P. Plasticity of Cancer Cell Invasion—Mechanisms and Implications for Therapy. In Advances in Cancer Research; Elsevier, 2016; Vol. 132, pp 209–264. https://doi.org/10.1016/bs.acr.2016.07.005.
(40) Arboleda-Estudillo, Y.; Krieg, M.; Stühmer, J.; Licata, N. A.; Muller, D. J.; Heisenberg, C.-P. Movement Directionality in Collective Migration of Germ Layer Progenitors. Current Biology 2010, 20 (2), 161–169. https://doi.org/10.1016/j.cub.2009.11.036.